VIEWS IN FOCUS The Landscape of Human Cancer Proteins Targeted by SARS-CoV-2 Beril Tutuncuoglu 1 , 2 , 3 , 4 , 5 , Merve Cakir 1 , 2 , 3 , 4 , 5 , Jyoti Batra 1 , 2 , 3 , 4 , Mehdi Bouhaddou1 , 2 , 3 , 4 , 5 , Manon Eckhardt 1 , 2 , 3 , 4 , David E. Gordon 1 , 2 , 3 , 4 , and Nevan J. Krogan 1 , 2 , 3 , 4 , 5 Summary: The mapping of SARS-CoV-2 human protein–protein interactions by Gordon and colleagues revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identifi ed at the host–virus interface of SARS-CoV-2 to enable cancer biologists to apply their knowledge for rapid drug repur- posing to treat COVID-19, and help inform the response to potential long-term complications of the disease. INTRODUCTION tumor suppressors. On the basis of this, systemwide integra- tion of protein–protein interactions that drive viral pathogen- The global pandemic caused by SARS-CoV-2, starting in esis and tumorigenesis are promising to identify critical nodes 2019, places a heavy burden on public health systems and that drive deregulation of cellular mechanisms. causes widespread suffering. Analysis aimed to identify com- Prompted by the urgency of the SARS-CoV-2 pandemic, mon pathways hijacked by the virus and other diseases has hundreds of researchers came together and formed the QBI the potential for rapid repurposing of clinically available Coronavirus Research Group (QCRG) at the University of drugs to treat COVID-19, while informing us of potential California, San Francisco, and neighboring institutions. As long-term complications of coronavirus infection. Knowl- a concerted effort of the QCRG, we mapped a network of edge about pathways implicated across different diseases will virus–host protein–protein interactions by purifi cation of 26 facilitate this task by allowing invaluable input from experts of the 29 SARS-CoV-2 proteins, followed by mass spectrometry in other fi elds, such as cancer biologists and physicians. analysis ( 1 ). This analysis revealed 332 human proteins that are In order to replicate, viruses have evolved ways to target targeted by SARS-CoV-2. In addition, we identifi ed 69 FDA- and manipulate key molecular mechanisms with a minimal approved drugs or compounds in clinical trials and preclinical number of proteins. Studying the specifi c pathways that are development that could be repurposed for inhibition of identi- commonly hijacked by viruses might provide information fi ed virus–host protein–protein interactions. Here, we summa- on functional hubs of cellular protein interaction networks. rize the common pathways of various cancers with those that For example, viruses can manipulate the cell cycle, recruit are targeted by SARS-CoV-2, as identifi ed by QCRG. Among host DNA-damage machinery to replication sites, hijack host the identifi ed human proteins, we annotated 46 proteins that translation machinery, interfere with apoptosis by suppressing are either known or candidate cancer genes by Cancer Gene signaling pathways, and reprogram host epigenetic markers to Census ( 2 ) and Network of Cancer Genes ( 3 ). Among the antagonize immune responses. Besides being essential for opti- identifi ed compounds, 23 of them are used or investigated in mal functioning of a cell, these same critical pathways are per- clinical trials for cancer treatment ( Fig. 1 ; Supplementary Table turbed in cancer cells. Both cancer cells and pathogens exploit S1). Here, we highlight the specifi c factors that were previously similar molecular mechanisms to manipulate apoptosis and shown to be involved in cancer pathology in these pathways. evade host immunity. The evidence for shared viral targets and cancer drivers comes from reported cases where a history of infection with certain RNA or DNA viruses is associated with CELL CYCLE AND DNA DAMAGE oncogenesis by activating cellular oncogenes or repressing Dysregulation of cell-cycle control is one of the hallmarks of cancer, as cancer cells continue to proliferate through altera- 1 Department of Cellular and Molecular Pharmacology, University of Cali- tion of processes that provide sustained growth signaling and fornia, San Francisco, California. 2 The J. David Gladstone Institutes, San enable evasion of cell-cycle arrest and apoptosis. As survival Francisco, California. 3 Quantitative Biosciences Institute, University of of viruses relies on the ability to replicate in host cells, it is 4 California, San Francisco, California. QBI COVID-19 Research Group not surprising that they also interfere with the host cell-cycle (QCRG), San Francisco, California. 5 The Cancer Cell Map Initiative (CCMI), University of California, San Francisco, California, and University of Cali- machinery. Viruses can arrest or promote cell-cycle progres- fornia, San Diego, La Jolla, California. sion. For example, Simian Virus 40 enhances progression into Note: Supplementary data for this article are available at Cancer Discovery S-phase to promote replication of the viral DNA genome ( 4 ). Online (http://cancerdiscovery.aacrjournals.org/). In contrast, infection with the avian corona virus Infectious Corresponding Author: Nevan J. Krogan, University of California, San Bronchitis Virus (IBV) induces G 2 –M phase arrest to enhance Francisco, 1700 4th Street, Room 308D, San Francisco, CA 94158. progeny virus production ( 5 ). In the SARS-CoV-2 interactome, Phone: 415-476-2980 ; E-mail: [email protected] we identifi ed a variety of proteins with roles related to cell- Cancer Discov 2020;10:916–21 cycle progression, especially proteins associated with the cen- doi: 10.1158/2159-8290.CD-20-0559 trosome, mitotic spindle, and regulation of cytokinesis ( 1 ). As © 2020 American Association for Cancer Research. expected, these interactions occur with viral proteins involved 916 | CANCER DISCOVERY JULY 2020 AACRJournals.org VIEWS Valproic acid Nuclear pore DNA polymerase α ACSL3 HDAC2 CYB5R3 NUP54 NUP62 PRIM1 POLA1 GIGYF2 EIF4E2 Metformin NDUFAF2 NUP214 NSP7 NUP88 PRIM2 POLA2 CYB5B NSP5 Dabrafenib NUP58 NEK9 NSP2 Electron NSP1 transport GNG5 NSP9 RHOA GNB1 RAP1GDS1 GPCR signaling SPART FBN2 NSP8 NDUFAF1 FBLN5 HMOX1 NSD2 Electron ECSIT transport ACAD9 Fibrillin FBN1 DDX10 ORF3a NDUFB9 HECTD1 Mycophenolic acid Ponatinib Centrosome IMPDH2 RIPK1 MYCBP2 ORF9c CEP68 LARP4B CNTRL SIRT5 NSP12 TCF12 CRTC3 CEP43 NIN TYSND1 AKAP8 CEP350 Protein kinase A NSP14 Rapamycin NINL signaling Sapanisertib RNA processing AKAP9 PRKACA Zotatifin PABPC4 LARP1 CEP250CEC Tomivosertib PCNT PRKAR2A PABPC1 CEP135CEPP1353 RRP9 MOV10 CDK5RAP2 PRKAR2B UPFPF1 CEP112P11212 GOLGA2 RPL36 CENPF RBM2R M2M 8 GOLGA3 DDX21 GOLGB1 ZYG11B GORASP1 ELOC ERC1 NSP13 N GCC2 PDE4DIP ELOB GCC1 USP13 CSNK2B RBX1 TBK1 Golgi ORF10 TLE1 organization CSNK2A2 G3BP1 CUL2 CUL2 Silmitasertib G3BP2 complex TLE5 TLE3 Stress granule regulation Pevonedistat Transcriptional ABBV-744 Azacitidine CPI-0610 DNMT1 regulation CSDE1 SLC9A3R1 BRD2 PCSK6 HS6ST2 BRD4 Midostaurin NUP98 CHPF ORF8 Ruxolitinib ORF9b RAE1 CHPF2 MARK kinase E signaling ORF6 Glycosaminoglycan MARK3 Nuclear synthesis MARK2 pore MARK1 Selinexor Cell cycle/ 1.0 Metabolism SARS-CoV-2 viral protein MIST score 0.7 DNA damage Human protein 181 Protein complex/ Translation/ Epigenetics/ Human–human protein–protein interaction 2 Spectral count biological process RNA processing chromatin Figure 1. Cancer genes interacting with SARS-CoV-2. Known and candidate cancer genes are selected from the interactome of 26 SARS-CoV-2 proteins using Cancer Gene Census and Network of Cancer Genes databases (black) and literature review (gray). Proteins that are in the same protein complexes or processes with potential cancer genes are shaded. Currently cancer drugs that are currently used or in clinical trials Mist Score and Spectral Count of protein–protein interactions are based on the values obtained from the SARS-CoV-2-human protein–protein interaction map (1). See Supplementary Table S1 for the full list of drugs. in replication of the viral genome: NSP7 is an essential cofac- approved or undergoing clinical trials can be effective against tor of the RNA-dependent RNA polymerase, NSP9 binds these proteins. Dabrafenib, a medication for the treatment single-stranded RNA, and NSP13 is a helicase/triphosphatase. of BRAF-associated cancers, is predicted to inhibit NEK9, Among these are 12 centrosome-associated proteins, protein an interactor of NSP9. In addition, the activity of RIPK1, an A-kinase (PKA) signaling components as well as proteins with NSP12 interactor which is associated with apoptosis, necrop- roles in the regulation of mitotic progression and cytokinesis tosis, and inflammatory pathways, is predicted to be inhibited (Fig. 1, yellow highlights). Cell-cycle machinery is a common by ponatinib and pazopanib. However, it is important to keep target for cancer treatment, and our chemoinformatic analy- in mind that some of these proteins promote cell survival or ses revealed that certain anticancer agents that are already death depending on the context. For example, in vitro studies JULY 2020 CANCER DISCOVERY | 917 VIEWS in the African green monkey kidney epithelial Vero E6 cell (7). Our network revealed interactions with this pathway, for line revealed that ponatinib treatment results in decreased cell example, an interaction between ORF3a and HMOX1, as well viability in higher doses and may result in slightly increased as NSP14 and SIRT5. Interestingly, NFE2L2 binds to HMOX1 infection to the cells (1). This result is somewhat expected promoter and activates its expression. The